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Dmp1 Promoter-Driven Diphtheria Toxin Receptor Transgene Expression Directs Unforeseen Effects in Multiple Tissues
Mice harbouring a dentin matrix protein 1 (Dmp1) promoter-driven human diphtheria toxin (DT) receptor (HDTR) transgene (Tg) have recently been used to attain targeted ablation of osteocytes by diphtheria toxin (DT) treatment in order to define osteocyte function. Use of these Tg mice has asserted me...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5297664/ https://www.ncbi.nlm.nih.gov/pubmed/28035954 http://dx.doi.org/10.3390/ijms18010029 |
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author | Al-Jazzar, Ahmed Javaheri, Behzad Prideaux, Matt Boyde, Alan Scudamore, Cheryl L. Cherifi, Chahrazad Hay, Eric Hopkinson, Mark Boyd, Michael Cohen-Solal, Martine Farquharson, Colin Pitsillides, Andrew A. |
author_facet | Al-Jazzar, Ahmed Javaheri, Behzad Prideaux, Matt Boyde, Alan Scudamore, Cheryl L. Cherifi, Chahrazad Hay, Eric Hopkinson, Mark Boyd, Michael Cohen-Solal, Martine Farquharson, Colin Pitsillides, Andrew A. |
author_sort | Al-Jazzar, Ahmed |
collection | PubMed |
description | Mice harbouring a dentin matrix protein 1 (Dmp1) promoter-driven human diphtheria toxin (DT) receptor (HDTR) transgene (Tg) have recently been used to attain targeted ablation of osteocytes by diphtheria toxin (DT) treatment in order to define osteocyte function. Use of these Tg mice has asserted mechano- and novel paracrine regulatory osteocyte functions. To explore osteocyte roles fully, we sought to confirm the selectivity of DT effects in these transgenic mice. However, our findings revealed incomplete DT-induced osteocyte ablation, prevalent HDTR misexpression, as well as more prominent histopathological DT-induced changes in multiple organs in Tg than in wild-type (WT) littermate mice. Mechanistic evidence for DT action, via prominent regulation of phosphorylation status of elongation factor-2 (EF-2), was also found in many non-skeletal tissues in Tg mice; indicative of direct “off-target” DT action. Finally, very rapid deterioration in health and welfare status in response to DT treatment was observed in these Tg when compared to WT control mice. Together, these data lead us to conclude that alternative models for osteocyte ablation should be sought and caution be exercised when drawing conclusions from experiments using these Tg mice alone. |
format | Online Article Text |
id | pubmed-5297664 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-52976642017-02-10 Dmp1 Promoter-Driven Diphtheria Toxin Receptor Transgene Expression Directs Unforeseen Effects in Multiple Tissues Al-Jazzar, Ahmed Javaheri, Behzad Prideaux, Matt Boyde, Alan Scudamore, Cheryl L. Cherifi, Chahrazad Hay, Eric Hopkinson, Mark Boyd, Michael Cohen-Solal, Martine Farquharson, Colin Pitsillides, Andrew A. Int J Mol Sci Article Mice harbouring a dentin matrix protein 1 (Dmp1) promoter-driven human diphtheria toxin (DT) receptor (HDTR) transgene (Tg) have recently been used to attain targeted ablation of osteocytes by diphtheria toxin (DT) treatment in order to define osteocyte function. Use of these Tg mice has asserted mechano- and novel paracrine regulatory osteocyte functions. To explore osteocyte roles fully, we sought to confirm the selectivity of DT effects in these transgenic mice. However, our findings revealed incomplete DT-induced osteocyte ablation, prevalent HDTR misexpression, as well as more prominent histopathological DT-induced changes in multiple organs in Tg than in wild-type (WT) littermate mice. Mechanistic evidence for DT action, via prominent regulation of phosphorylation status of elongation factor-2 (EF-2), was also found in many non-skeletal tissues in Tg mice; indicative of direct “off-target” DT action. Finally, very rapid deterioration in health and welfare status in response to DT treatment was observed in these Tg when compared to WT control mice. Together, these data lead us to conclude that alternative models for osteocyte ablation should be sought and caution be exercised when drawing conclusions from experiments using these Tg mice alone. MDPI 2016-12-26 /pmc/articles/PMC5297664/ /pubmed/28035954 http://dx.doi.org/10.3390/ijms18010029 Text en © 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Al-Jazzar, Ahmed Javaheri, Behzad Prideaux, Matt Boyde, Alan Scudamore, Cheryl L. Cherifi, Chahrazad Hay, Eric Hopkinson, Mark Boyd, Michael Cohen-Solal, Martine Farquharson, Colin Pitsillides, Andrew A. Dmp1 Promoter-Driven Diphtheria Toxin Receptor Transgene Expression Directs Unforeseen Effects in Multiple Tissues |
title | Dmp1 Promoter-Driven Diphtheria Toxin Receptor Transgene Expression Directs Unforeseen Effects in Multiple Tissues |
title_full | Dmp1 Promoter-Driven Diphtheria Toxin Receptor Transgene Expression Directs Unforeseen Effects in Multiple Tissues |
title_fullStr | Dmp1 Promoter-Driven Diphtheria Toxin Receptor Transgene Expression Directs Unforeseen Effects in Multiple Tissues |
title_full_unstemmed | Dmp1 Promoter-Driven Diphtheria Toxin Receptor Transgene Expression Directs Unforeseen Effects in Multiple Tissues |
title_short | Dmp1 Promoter-Driven Diphtheria Toxin Receptor Transgene Expression Directs Unforeseen Effects in Multiple Tissues |
title_sort | dmp1 promoter-driven diphtheria toxin receptor transgene expression directs unforeseen effects in multiple tissues |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5297664/ https://www.ncbi.nlm.nih.gov/pubmed/28035954 http://dx.doi.org/10.3390/ijms18010029 |
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